HU227126B1 - Use of cyclooxygenase-2 inhibitors for producing pharmaceutical compositions suitable for the treatment and prevention of tumors, tumor-veloted disorders and cachexia - Google Patents

Description

Scope of the description is 14 pages (including 1 page figure)

22 227 126 1

The present invention relates to the use of certain compounds, in particular cyclooxygenase-2 inhibitors (hereinafter referred to as "COX-2 inhibitors") in the manufacture of a medicament for the treatment and prevention of tumors and tumor-related disorders and obesity (latinosan: cachexia).

Cachexia is a systemic disease in which the most important symptoms include gradual weight loss, anemia, edema, and loss of appetite. It may be a side effect of certain chronic diseases such as malignant tumors, tuberculosis, diabetes, diseases of the blood system, endocrine diseases, infections and immunodeficiency syndrome (AIDS). If cachexia occurs as a result of a malignant tumor, even if the treatment of malignant tumor is effective due to the use of antitumor agents administered to the patient and there is evidence of antitumor activity, there is usually no improvement in the cachexia by such an anti-tumor agent. such as myelotoxicity, ie the destructive effect on the spinal cord.

The treatment of cachexia is often very difficult for the following reasons.

Considering that the patient's resistance is greatly impaired as cachexia progresses, it is often impossible to continue treatment with anti-tumor agents (which usually produce high toxicity) and hence the treatment of malignant tumors is hampered.

Nutritional additives are often used to treat the symptoms of cachexia. However, this often contributes to the development of a malignant tumor and can thus reduce the patient's survival time.

Currently, there is no satisfactory method of treating cachexia, so there is a growing need for the treatment of symptoms of cachexia in the medical field.

The following compounds of formula (I) or (II), which together with some other compounds form the active ingredients of the pharmaceutical compositions of the invention, are known to selectively inhibit the cyclooxygenase-2 (COX-2) enzyme. It is also known that these compounds are capable of inhibiting the formation of anti-inflammatory cytokines (in particular IL-1 and TNF-α), the production of leukotriene (more particularly LTB ₄ ), bone resorption, analgesic, anti-inflammatory and antipyretic (see Fig. 799). European Patent Publication No. 823A).

However, it is not known that these compounds could be used to treat or prevent cachexia.

However, although it is known that some of the additional active ingredients of the present invention, in particular the compounds of formulas III and IV, have selective inhibitory effects on cyclooxygenase-2, they have inhibitory activity against inflammatory cytokines (more particularly IL-1 and TNF-α). for the production of leukotrienes (more particularly, LTB ₄ ), inhibit bone resorption, and have analgesic, anti-inflammatory and antipyretic effects [WO 95/00501, J. Med. Chem., 41, 1347 (1997); WO 94/13635; Pharmacology, 55, 44 (1997); Prostaglandins, 47, 55 (1994); Hei 9-52882 (Kokai); Jpn. J. Pharmacol., 67, 305 (1995); Inflamm. Slit., 47, Suppl. 3, 257 (1997); J. Med. Chem., 38, 4570 (1995); U.S. Patent No. 5,474,995; European Patent No. 863,134; and WO 98/06708, however, it has not been known that these compounds would be effective against cachexia.

Epidemiological studies have shown that there is an inverse correlation between the use of certain conventional non-steroidal anti-inflammatory drugs, which are COX-1 and COX-2 inhibitors, the so-called conventional NSAIDS agents (most commonly known as aspirin) and intestinal cancer. There are also numerous publications suggesting that NSAIDS, such as aspirin and sulindac, have inhibitory effects on tumor metastases and carcinogenesis in preclinical studies. Some NSAIDS agents have been used to prevent colon carcinogenesis in clinical trials.

However, given that these conventional NSAIDS agents are not selective for COX-1 or COX-2, adverse side effects are unavoidable.

Therefore, the development of a selective cyclooxygenase-2 inhibitor (a selective COX-2 inhibitor) as an antitumor agent with a reduced incidence of said adverse effects would be very advantageous.

Known selective COX-2 inhibitors are known to be MF tricydic (Oshima, M. et al., "Suppression of Intestinal Polyposis in APCA ⁷¹⁶ Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)", Cell, 87, 803 -809 (1996)] and celecoxib [Reddy, RS et al., Evaluation Evaluation Cyclooxygenase-2 Inhibitor Forum Potential Chemopreventive Properties in Colon Carcinogenesis, Cancer Rés., 56, 4566-4569 (1996)] inhibit experimental colonic polyposis (the presence of multiple polyps), and it is also known that substance SC-58125 exhibits growth inhibitory activity for certain human colon cancer cell lines (Sheng, H. et al., "Inhibition of Human Colon Cancer Cell Growth by Selective Inhibition of Cyclooxygenase"). -2 ”, J. Clin. Invest., 99: 2254-2259 (1997)].

However, for the compounds listed in the previous paragraph, the experimental system used is not a model of an advanced colon cancer, and

Vegyületek1 said compounds are suitable only for the prevention of polyposis occurring in the early stages of colon cancer.

On the other hand, for the compounds disclosed by Sheng, H., et al., The only colon cancer cell line that has an inhibitory effect on growth was a cell line that expresses cyclooxygenase-2 (human colon cancer cell line HCA-7) and has been described. that in vitro tumor cell growth inhibitory activity (HCT-116) does not inhibit tumor growth in vivo. Thus, the effect of a COX-2 inhibitory tumor inhibitory agent on in vitro colon cancer depends on whether the particular colon cancer cell line is in vitro susceptible to COX-2 inhibitory cell growth. Thus, the in vivo inhibitory effect of COX-2 inhibitors on tumor growth is unlikely to be observed against various other cancers, especially cancerous diseases, including colon cancer, which are resistant to in vitro COX-2 inhibitor-induced cell growth, or do not express cyclooxygenase-2.

It is further noted that the use of a combination of a selective cyclooxygenase-2 inhibitor and a 5-fluorouracil derivative has not been disclosed in the literature to prevent or inhibit cancer growth.

It has been discovered that certain 1,2-diphenylpyrrole derivatives and other compounds having close structural similarities are of high activity for the prevention or inhibition of cachexia, and that these 1,2-diphenylpyrrole derivatives are effective in treating or preventing tumor related disorders. alone or in combination with a 5-fluorouracil derivative.

Thus, the present invention relates to pharmaceutical compositions for treating or preventing cachexia in mammals, including humans, which contain as active ingredient an effective amount of a compound of formula (I) or (II) or a compound of formula (III) or (IV), or a pharmaceutically acceptable salt thereof. contain an acceptable salt thereof. The substituents or abbreviations used in said formulas are as follows:

R ¹ is amino or -NHR ^a and in the latter R ^a is an in vivo eliminable alkanoyl group;

R ² is phenyl or phenyl substituted with at least one substituent selected from α-substituents and β-substituents as defined below;

R ⁴ is C 1-6 alkyl; the α-substituents are C 1-6 alkoxy and C 1-6 alkylthio; and β-substituents are C 1-6 alkyl.

The invention further relates to pharmaceutical compositions which are useful for treating or preventing mammalian, including human tumor related disorders, and which contain, according to the invention, an active ingredient selected from the group consisting of compounds of formula (I) and (II) as defined above.

Preferred compounds of the present invention are those of formula (I) and (II) wherein the substituents are as follows:

(1) R ¹ is amino or acetylamino;

(2) R ² is phenyl or phenyl substituted with 1 to 3 substituents as previously defined.

When R ⁴ or β is alkyl having 1 to 6 carbon atoms, the alkyl moiety may be straight or branched. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, and the like. 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2 , 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl. Among these groups, straight-chain or branched alkyl groups having 1 to 4 carbon atoms are preferred, more preferably methyl and ethyl. In the meaning of R ^4, the alkyl group is particularly preferably methyl.

When R ^a is an alkanoyl, it may be a straight or branched alkanoyl group having 1 to 25 carbon atoms. Examples of such groups include: formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, palmitoyl, stearoyl, icosanoyl, docosananyl and pentacosanoyl. Among these groups, preferred are C 1-12 alkanoyl, more preferably C 1-6 alkanoyl, even more preferred are C 1-4 alkanoyl and most preferred are acetyl and propionyl. This group can be eliminated by an inactive group, so such a group may be a group that can be eliminated by physiological conditions in the human body, e.g., by hydrolysis, i.e. a group which gives a free amino group (-NH ₂ ) from ^the group -NHR ^a (in this wherein R ^a is as defined above. It is easy to determine whether a particular group can be eliminated or not in the following experiment: The test compound is administered orally or intravenously to an experimental animal, such as a rat or mouse, and the body fluid is examined for the corresponding free amino group compound or a pharmaceutically acceptable compound thereof. the presence or absence of a salt thereof.

22 227 126 1

When the substituent is a C1-C6 alkoxy group, it may be straight-chain or branched. Examples include the following groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylsulf, 2-methylbutoxy , neopentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentylsulf, 2-methylpentyloxy, 1- methyl pentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy. Of these, straight or branched chain alkoxy groups having 1 to 4 carbon atoms are preferred, more preferably methoxy and ethoxy.

When the substituent is an alkylthio group having from 1 to 6 carbon atoms, it may be straight or branched. Examples of such groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio -, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1 1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio -group. Among these groups, straight-chain or branched alkylthio groups having 1 to 4 carbon atoms are preferred, more preferably methylthio and ethylthio.

Preferred groups in R ¹ include amino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, acetoxymethylamino, propionyloxymethylamino, methoxycarbonyloxymethylamino, ethoxycarbonyloxymethylamino, (5-methyl -2-oxo-1,3-dioxolen-4-yl) methylamino (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl-amino. The most preferred are amino and acetylamino.

Specific examples of R ² include: unsubstituted phenyl;

Phenyl groups substituted with substituents selected from C 1-4 alkoxy groups and C 1-4 alkylthio groups, such as ρ-tolyl, 4-ethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl 4-Methylthiophenyl, 4-ethylthiophenyl, 3,4-dimethoxyphenyl, 3-methyl-4-methoxyphenyl and 4-methoxy-3,5-dimethylphenyl -group.

When R ² is substituted phenyl, the number of substituents is preferably 1, 2 or 3, more preferably 1 or 2.

In R ^4, specific examples of C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Preferred examples of R ⁴ include alkyl having 1-4 carbon atoms, such as methyl, ethyl, isopropyl, butyl and isobutyl.

Certain compounds of the invention, in particular compounds of formulas (I) and (II), contain acidic groups and can form salts with cations. The nature of the salt is not relevant to the invention, provided that the salt is pharmaceutically acceptable, i.e. the salt is not active (or unacceptably low) or non-toxic (or unacceptably toxic) than the corresponding free acid. Examples of such salts include salts with alkali metals such as sodium, potassium or lithium; salts with alkaline earth metals such as calcium or magnesium; salts with other metals, such as aluminum, iron, zinc, copper, nickel or cobalt; other inorganic salts such as ammonium salts; organic amines such as 1-octylamine, dibenzylamine, morpholine, glucose amine, phenylglycine alkyl esters, ethylene diamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, Salts with N'-dibenzyl ethylene diamine, chloroprocaine, procaine, diethanolamine, N-benzylN-phenethylamine, piperazine, tetramethylammonium methane or tris (hydroxymethyl) aminomethane.

Furthermore, when the compounds of the formulas I and II and their salts are left in the atmosphere, they can adsorb moisture to form hydrates. Such hydrates are also contemplated as being within the scope of the present invention.

Furthermore, the compounds of the formulas I and II and their salts may, in some cases, absorb various solvents to form solvates, such solvates being considered within the scope of the invention.

Certain compounds of formulas (I) and (II) may contain asymmetric carbon atoms in their molecules, so that they may exist as stereoisomers having the R configuration or S configuration. These stereoisomers and mixtures thereof in any proportion are also considered to be within the scope of the invention.

Specific examples of the compounds of formula (I) and (II) according to the invention are listed in the following Table 1 (compounds of formula I):

In Table 2 [Compounds of Formula II], the following abbreviations are used in the tables:

Ac acetyl; Bu butyl; Byr butyryl; ÍByr isobutyryl; bz benzyl; et ethyl; for CHO; Me methyl; F phenyl; Piv pivaloyl; pr Pr; IPR isopropyl; prn propionyl; with isovaleryl; and With valeryl.

22 227 126 1

Table 1

The food. number R ¹ R ² R ⁴ 1-1. nh ₂ Ph Me 1-2. hn ₂ 4-MeO-Ph Me 1-3. hn ₂ 4-MeO-Ph Bu 1-4. hn ₂ 4-EtO-Ph Me 1-5. hn ₂ 4-Ph-PrO Me 1-6. hn ₂ 4-MeS-Ph Me 1-7. hn ₂ 4-Me-Ph Me 1-8. hn ₂ 3-Me-4-MeO-Ph Me 1-9. hn ₂ 3,4-diMeO-Ph Me 1-10. hn ₂ 3,4-di (MeO) -Ph Me 1-11. hn ₂ 4-Et-Ph Me 1-12. hn ₂ 2,4,6-trim-Ph Me 1-13. hn ₂ 4-ETS Ph Me 1-14. NHFor 4-MeS-Ph Me 1-15. NHAc 4-MeS-Ph Me 1-16. NHPrn 4-MeS-Ph Me 1-17. NHByr 4-MeS-Ph Me 1-18. NhiByr 4-MeS-Ph Me 1-19. NHVal 4-MeS-Ph Me 1-20. NHiVal 4-MeS-Ph Me 1-21. NHPiv 4-MeS-Ph Me

Table 2

The food. number R ¹ R ² R ⁴ 2-1. nh ₂ 4-MeO-Ph Me 2-2. nh ₂ 4-MeO-Ph et 2-3. nh ₂ 4-EtO-Ph Me 2-4. nh ₂ 4-Ph-PrO Me 2-5. nh ₂ 4-MeS-Ph Me 2-6. nh ₂ 4-Me-Ph Me 2-7. hn ₂ 4-Et-Ph Me 2-8. nh ₂ 4-Ph-Pr Me 2-9. nh ₂ 3-Me-4-MeO-Ph Me 2-10. nh ₂ 3,4-diMeO-Ph Me 2-11. nh ₂ 3,4-di (MeO) -Ph Me 2-12. nh ₂ 3,5-dimethyl-4-MeO-Ph Me 2-13. nh ₂ 2,4,5-trim-Ph Me 2-14. hn ₂ 2,4-diMeO-Ph Me 2-15. nh ₂ 3,5-diMeO-Ph Me 2-16. NHAc 4-MeO-Ph Me 2-17. NHAc 3,4-diMeO-Ph Me 2-18. NHFor 4-MeO-Ph Me 2-19. NHPrn 4-MeO-Ph Me 2-20. NHByr 4-MeO-Ph Me

22 227 126 1

Table 2 (continued)

The food. number R ¹ R ² R ⁴ 2-21. NhiByr 4-MeO-Ph Me 2-22. NHVal 4-MeO-Ph Me 2-23. NHiVal 4-MeO-Ph Me 2-24. NHPiv 4-MeO-Ph Me 2-25. NHFor 4-EtO-Ph Me 2-26. NHAc 4-EtO-Ph Me 2-27. NHPrm 4-EtO-Ph Me 2-28. NHByr 4-EtO-Ph Me 2-29. NhiByr 4-EtO-Ph Me 2-30. NHVal 4EtO-Ph Me 2-31. NHiVal 4-EtO-Ph Me 2-32. NHPiv 4-EtO-Ph Me 2-33. NHFor 3,4-diMeO-Ph Me 2-34. NHPrn 3,4-diMeO-Ph Me 2-35. NHByr 3,4-diMeO-Ph Me 2-36. NhiByr 3,4-diMeO-Ph Me 2-37. NHVal 3,4-diMeO-Ph Me 2-38. NHiVal 3,4-diMeO-Ph Me 2-39. NHPiv 3,4-diMeO-Ph Me

Among the compounds listed above, we prefer:

1.4-Methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole,

2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

3. 1- (4-Methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;

4. 4-Ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) pyrrole;

5. 4-Methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole;

6. 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

7. 2- (4-Methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

8. 4-Methyl-2-phenyl-1- (4-sulfamoylphenyl) pyrrole;

9. 2- (3,4-Dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;

10. 4-Methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;

11.1 - (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyridine,

12. 1- (4-Ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole,

13. 2- (3,5-Dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;

14. 1- (4-acetylamino-sulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and

15. 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl-pyrrole).

Among the preferred compounds listed above, the following compounds are more preferred:

1.4-Methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole,

2. 2- (4-Methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

5. 4-Methyl-2- (4-methyl-thiophenyl) -1- (4-sulfonamoyl) -pyrrole;

6. 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

7. 2- (4-Methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

9. 2- (3,4-Dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;

10. 4-Methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;

14. 1- (4-acetylamino-sulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and

15. 1- (4-Acetylamino-sulfonyl-1-phenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole.

The most preferred of these are:

6. 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole,

9. 2- (3,4-Dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;

10. 4-Methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;

14. 1- (4-acetylamino-sulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and

15. 1- (4-Acetylamino-thienone-1-phenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole.

The compounds of formula (I), the compounds of formula (II) and the pharmaceutically acceptable salts thereof are known compounds and are prepared by the method of

EP-799823A.

22 227 126 1

The chemical names of compounds (III) and (IV) are as follows:

(III): 3- (3,4-Difluoro-phenyl) -4- (4-methanesulfonyl-phenyl) -5H-furan-2-one, (IV): 4- (5-p-tolyl-3-trifluoromethyl) -1H-pyrazol-1-yl) benzenesulfonamide.

These compounds are known from WO 95/00501, J. Med. Chem., 40, 1347 (1997); WO 94/13635; Pharmacology, 55, 44 (1997); Prostaglandins, 47, 55 (1994); Hei 9-52882 (Kokai); Jpn. J. Pharmacol., 67, 305 (1995); Inflamm. Slit., 47, Suppl. 3, S257 (1997); J. Med. Chem., 38, 4570 (1995); U.S. Patent No. 5,474,995; European Patent No. 863,134; and WO 98/06708.

Given that the compounds of the present invention have excellent activity in preventing or inhibiting cachexia, but have a low toxicity, they can be used to prevent and cachexia. They are also useful for treating tumor related disorders of the present invention, as well as inhibiting tumor growth and / or metastasis.

If desired, one or more of the compounds of the invention, i.e. one or more of the compounds of formula (I) to (IV), may be used together with one or more of the other active ingredients for preventing or inhibiting the growth of tumors, and the compounds of the present invention or these additional active ingredients may be administered simultaneously , separately or sequentially.

Further anti-tumor agents are preferably 5-fluoracil, cisplatin, tamoxifen, paclitaxel, docetaxel and ironotecan. In particular, for simultaneous administration, the compounds of formula (I) or (II) of the present invention or their pharmaceutically acceptable salts and the additional anti-tumor agent may be used in a single composition.

The pharmaceutical compositions of the present invention may be in any conventional form, depending on the route of administration. For example, for oral administration, tablets, capsules, granules, powders, or syrups may be used. In the case of non-oral administration, injections or suppositories may be used. These pharmaceutical compositions can be prepared in a manner well known in the art. However, such pharmaceutical compositions are well-known carriers and / or other excipients such as excipients (e.g., organic excipients, including sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch). and dextrin; cellulose derivatives such as crystalline cellulose, gum arabic, dextran, and pullulan; phosphates, carbonates such as calcium carbonate, and sulfates such as calcium sulfate); lubricants such as stearic acid and its metal salts such as stearic acid itself, calcium stearate and magnesium stearate; talc; colloidal silicon dioxide; waxes such as beeswax and sputum; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; Sodium benzoate; DL-leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicas such as silicic anhydride and silicic acid hydrate; and starch derivatives mentioned above); binders such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Macrogol and the like; disintegrating agents (e.g., cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethylcellulose, internally bridged sodium carboxymethyl cellulose); chemically modified starch celluloses such as carboxymethyl starch, sodium carboxymethyl starch and bridged polyvinylpyrrolidone); stabilizers such as parahydroxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic; and sorbic acid); flavoring agents (such as sweeteners, vinegar and perfumes); and may contain diluents.

The dose employed in a particular case will depend on a number of factors, including the condition and age of the patient, the severity and nature of the disorder, and the route of administration. For example, in the case of oral administration to adults, an amount of 0.01 mg / kg of body weight, preferably 0.1 mg / kg of body weight as lower limit and 50 mg / kg of body weight, preferably 10 mg / kg of body weight, is preferably added daily in single or divided doses, depending on the symptoms. In the case of intravenous administration, an amount of 0.001 mg / kg body weight, preferably 0.01 mg / kg body weight, as lower limit and 10 mg / kg body weight, preferably 5 mg / kg body weight, is preferably administered to an adult in a single or divided dose depending on the symptoms.

The invention is further illustrated by the following Examples and Examples of Preparation without limiting the scope of the invention.

Example 1: Study of the effect of cachexia in mice bearing Mouse Colon Cancer Colon 26 cells Experimental animals were 8 week female DCFI mice using groups of 10-10 animals for each experiment. Each animal was subcutaneously implanted subcutaneously with 1-10 ⁶ mouse colon cancer colon 26 cells.

As experimental compound mentioned in Table 1

1-6. or a compound of formula 2-3 as mentioned in Table 2; Compound No. 5 is used.

22 227 126 1

Each test compound was suspended in sterilized distilled water containing 0.5% (w / v) carboxymethylcellulose (CMC) and then orally administered once a day starting on the day of transplantation of tumor cells.

The weight of each test animal was measured directly after transplantation of tumor cells, and this value (A g) was recorded. All experimental animals were weighed again on day 19 after tumor cell transplantation and recorded (Bg). Body weight gain, measured on day 19 post tumor transplant, was calculated as BA = Ag _t for each experimental animal. The experimental series were repeated with two control groups, tumor cells were transplanted for the first control group (control group 1) but not treated with any of the test compounds, and the weight gain measured as Ag _{c1 was} reported, while the second control group (control group 2) was administered. ), tumor cells are not transplanted and no starting compound is treated, and the resulting weight gain is recorded as the Ág _c2 value. The weight retention ratio is calculated using the following formula, taking into account the body weight measured on the 19th day after transplantation of tumor cells, and this retention rate is considered as an indicator of cachexia activity.

Body Mass Retention Rate (%) = (Ag _t -Ag _c1 ) / (Ag _c2 -Ag _c1 ) -100

The results obtained are shown in Table 3.

Table 3

Compound injected Dose (Mg / kg) Weight growth (Branch) Weight Retention Rate (%) 2-3. compound 10 2.6 88 2-3. compound 3 2.5 88 2-3. compound 1 2.5 85 1-6. compound 10 3.1 98 1-6. compound 3 2.7 89 1-6. compound 1 2.2 78 Control Group 1 - -1.4 0 Control Group 2 - 3.2 100

From the above results, it is evident that the compounds of the invention inhibit cachexia in tumor mice and reduce weight loss.

Example 2: Investigation of the effect of cachexia in mice bearing Mouse Colon Cancer Colon 26 cells \ t

The method described in Example 1 was repeated, but the compound of formula (III) was used as the experimental compound and compared with the compound of formula (III) treated in the experimental group of animals treated _with the anti-tumor compound but transplanted with tumor cells. with control weight gain (Ag _c ). Experimental animals were 16 week old female CDF1 mice. Weight gain was measured on the 22nd day after tumor transplantation. Immediately after tumor transplantation, the average body weight of some groups of animals is 25-26 g. The results obtained are given in Table 4.

Table 4

Experimental compound Dose (Mg / kg) Average Weight Loss (Ag) Compound (III) 10 0.9 Compound III 3 0.3 Compound III 1 0.0 control Group - -4.2

From the above results, it is obvious that the compound of formula (III) inhibits cachexia caused by the tumor in mice or reduces weight loss.

EXAMPLE 3 Investigation of the Effect of Cachexia on Mouse Colon Cancer Colon 26 Mice Performed in Example 2, but using Compound IV as a Test Compound and Comparing with Compound IV. in the experimental group of animals, weight gain (Ag _t ) in the control group was measured by body weight gain (Ag _c ) at which tumor cells were transplanted, but no anti-tumor compound was used. As experimental animals, 7 weeks old female CDF1 mice were used. Weight gain was measured on day 15 after tumor transplantation. Immediately after tumor transplantation, the average body weight in some groups of experimental animals was 20-21 g. volt. The results obtained are given in Table 5.

Table 5

Experimental compound Dose (Mg / kg) Average Weight Loss (Ag) Compound IV 10 0.6 Compound IV 3 1.3 Compound IV 1 1.2 control Group - -3.4

From the above results, it is apparent that the compound of formula (IV) inhibits cachexia in the mice due to the tumor, or reduces weight loss.

22 227 126 1

Example 4

Investigating the lifetime activity

Observation of mice utilized in Example 1 was continued. The lifetime growth index is determined for each mouse based on the number of days of survival, and is used as an indicator of the lifetime effect of the test compounds.

It is noted that in the group of mice treated with the test compound, oral administration of the compound is continued once a day on day 20 after tumor cell transplantation and thereafter for a longer period of time.

Lifetime Increase Index (%) = (S _t / S _c -1) -100 S _t = mean survival days in the group of mice treated with the test compound S _c = mean value of survival days in the control group not transplanted with tumor cells

The results obtained are given in Table 6.

Table 6

Compound injected Dose (Mg / kg) Survival Time (Average: Days) Lifetime Increase Index (%) 2-3. compound 10 48.5 73 2-3. compound 3 50.5 80 2-3. compound 1 45.0 61 1-6. compound 10 45.0 61 1-6. compound 3 35.0 25 1-6. compound 1 48.5 73 control Group - 28.0 0

As can be seen from Table 6, the compounds of the invention specifically increase the average life span.

Example 5

Investigating the lifetime activity

The experiment described in Example 4 is carried out with the a

Experimental animals used in the assay of Example 2. In the group of mice treated with the test compound, oral administration of the compound was continued once a day on day 23 after tumor cell transplantation and thereafter. The results obtained are given in Table 7.

Table 7

Compound injected Dose (Mg / kg) Survival Time (Average: Days) Lifetime Increase Index (%) Compound III 10 43.5 91 Compound III 3 37.5 63 Compound III 1 40.5 76 - 23.0 -

Example 6

A series of experiments conducted with the concomitant use of an anti-tumor agent

As described in Example 1, CDF1 mice were transplanted with mouse colon cancer cells, followed by a compound of the invention [2-3. and 1-6. compound (III) and (IV)] and, on the other hand, 5-fluoroacyl or cisplatin as additional antitumor compounds.

The combination of a compound of the invention with a known anti-tumor agent has a significant inhibitory effect on tumor growth and cachexia, resulting in an increase in lifetime.

Example 7: Inhibitory effect of Mouse malignant melanoma B16-BL6 (mouse malignant melanoma) on lung metastasis induced by 8-10 week old female C57BL / 6 mice intravenously into the tail vein 3-10 ⁴ "mouse malignant melanoma B16-BL6 Transplant. If necessary, bacterial lipopolysaccharide (LPS) is administered intravenously to the tail vein intravenously in an amount of 3 to 3 µg one hour prior to transplantation of the melanoma cells to promote melanoma lung metastasis (Anasagasti, MJ et al., J. Natl. Cancer Research, 89: 645-651 (1997)].

The starting material is 2-10. Compound IV, Compound IV, and Indomethacin are suspended in 0.5% (w / v) carboxymethylcellulose (CMC) sterilized distilled water, and the suspension is administered orally at a dose of 1 mg / kg body weight per day for 5 days. melanoma cell transplantation day.

Referring to FIGS. compound 2- (3,4-dimethylphenyl) -4-methyl-1 (4-sulfamoylphenyl) pyrrole.

The inhibitory effect on lung metastasis of melanoma cells was evaluated as the lung metastasis inhibition rate (LMI%) by counting the number of metastatic colonies in the lung on the 10th day after intravenous transplantation of the mouse malignant melanoma B16-BL6 cells.

LMI% = (1-N _t / N _c ) -100

N _t: test compound treated group on day 10. The number of metastatic colonies in the lungs; and

N _c : the number of metastatic colonies in the lung on day 10 in the control groups not treated with the test compound.

The results obtained are shown in Table 8.

Table 8

Experimental compound LPS administration Dose (Mg / kg) LMI (%) 2-10. compound no 1 64 2-10. compound Yes 1 34

22 227 126 1

Table 8 (continued)

Experimental compound LPS administration Dose (Mg / kg) LMI (%) Compound IV Yes 1 9 Compound IV Yes 1 1 indomethacin Yes 1 -1

From the data in Table 8, it is clear that the compounds of the invention successfully inhibit the metastasis of mouse malignant melanoma B16-BL6 cells into the lung, regardless of whether it was stimulated by lung metastasis (induction of an inflammatory reaction).

More specifically, FIG. the compound exhibits a significant inhibitory effect on the formation of lung metastasis, whereas the compound of formula (IV), which is a selective inhibitor of COX-2, and indomethacin, a typical NSAID, does not exert such inhibitory activity under conditions inducing pulmonary metastasis induced by an inflammatory reaction ( these conditions actually simulate when tumor metastasis can be stimulated when a tumor is surgically excised).

Example 8: Antitumor activity against "Mouse sarcoma S-180" (mouse sarcoma) cells

In experimental groups of 10 to 10 animals, 8 week old female Balb / c hairless mice were subcutaneously implanted with T10 ⁶ mouse sarcoma S-180 cells.

The experimental compound, i.e., 2-118. The compound is suspended in 0.5% (w / v) carboxymethylcellulose (CMC) sterilized distilled water and administered orally once a day for 5 days following the day of transplantation of tumor cells.

Tumor activity is evaluated using the following equation to calculate the tumor growth inhibition rate (Gl%) on the 7th day after transplantation.

Gl (%) = (1-V _t / V _c ) -100

V _t: test compound treated groups at 7 days the mean tumor volume (*)

V _c : untreated control group on day 7, mean tumor volume (*) *: tumor volume is as follows: 1/2 [long axis of tumor longitudinal axis ytumor] ² The results are given in Table 9 below.

Table 9

Experimental compound Dose (Mg / kg) Gl (%) 2-10. Compound # 1 1 54

Example 9: Antitumor activity against human colon cancer KM 12-HX (human colon cancer) cells

As an experimental animal, groups of 10-10 individuals were used for 7 week female Balb / c hairless mice. They are blind to Fu et al. Fu et al., Anticancer Rés., 12 (1992)] transplant orthotopically " Human colon cancer KM12-HX " cells. In particular, under abacin anesthesia, incision is made in the lower left abdominal region of each mouse and a 5 mm thin tumor section is adhered to the appendix using an absorbable surgical suture as an orthotopic transplant. The incision is then sewn with an absorbable surgical suture, then the mice are heated and rapidly awakened from anesthesia. The test compound was suspended in sterilized distilled water containing 0.5% (w / v) carboxymethylcellulose (CMC) and then orally administered at a total of 9 doses after tumor transplantation 3-7. on days 10 to 13 after transplantation. once daily.

Tumor activity was evaluated based on the following equation to determine tumor growth inhibition ratio (Gl%) on day 14 post transplantation.

Gl (%) = (1-V _t '/ V _c ') -100

V _t ': mean weight of tumor in day 14 of the test compound treated group

V _c ': mean weight of tumor on day 14 in the untreated control group

The results obtained are given in Table 10.

Table 10

Experimental compound Dose (Mg / kg) Gl (%) 2-10. Compound # 1 0.3 12 2-10. Compound # 1 1 35 2-10. Compound # 1 3 45 2-10. Compound # 1 10 59

Table 10 shows that the compound of the invention inhibits the growth of human colon cancer cells at the site of orthotopic transplantation.

The following non-limiting compositions for the preparation of pharmaceutical compositions containing the compounds of the present invention will be described.

Preparation Example 1

capsules

A compound of the invention, for example, a compound of formula (III), is prepared, 1-6. Compound 2-3. Compound 2-10. a mixture of the compound with a digestible oily substance such as soybean oil, cottonseed oil or olive oil, and then pouring the mixture into gelatin

It can be seen from Table 9 that the compound of the invention inhibits the growth of tumor cells in mice.

EN 227 126 val1 with soft capsules containing 100-100 mg of the active ingredient. The capsules thus obtained are then washed and then dried.

Preparation Example 2

tablets

Tablets are prepared in a conventional manner in a quantity of 100 mg of a compound of the invention, such as a compound of formula III, 1-6. Compound 2-3. or compound 2-10. , 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose.

In this case, the tablets may be coated if desired.

Preparation Example 3

injections

1.5% by weight of a compound of the invention, such as the compound of formula III, 1-6. Compound 2-3. or compound 2-10. the compound is mixed with water containing 10% by volume propylene glycol and the final volume is adjusted with water for injection. Finally, sterilization is performed.

Preparation Example 4

suspensions

A suspension is prepared by administering 100 mg of a compound of the invention, e.g. Compound 2-3. or compound 2-10. The compound was mixed with fine powder and mixed with 5 ml of 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (Japanese pharmaceutical grade) and 0.025 ml of vanillin.

Claims (20)

PATENT CLAIMS 1. Compounds of formula (I) or (II) or compounds of formula (III) or (IV) R ¹ is amino or -NHR ^a , where R ^a is an in vivo eliminable alkanoyl group; R ² is phenyl or phenyl substituted with at least one substituent selected from the group consisting of α-substituents and β-substituents as defined below; R ⁴ is C 1-6 alkyl; the α-substituents are C 1-6 alkoxy and C 1-6 alkylthio; and the β-substituents are selected from the group consisting of C 1-6 alkyl groups and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of cachexia in a mammal. Use according to claim 1, wherein the active ingredient is a compound of formula (I) or (II). The use according to claim 2, wherein R ¹ is amino or acetylamino. Use according to claim 2, wherein the active ingredient is 4-methyl-2- (4-methylphenyl) -1- (4-sulphamoylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulphamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) - pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-Ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoyl) phenyl) pyrrole, 4-methyl-2-phenyl-1- (4-sulphamoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulphamoylphenyl) pyrrole, pyrrole 4-methyl-1- (4-methylthio-phenyl) -2- (4-sulfamoyl-phenyl), 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulphamoylphenyl) pyrrole, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3,5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (4-methoxy-phenyl) -pyrrole, and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. Use according to claim 2, wherein the active ingredient is 2- (4-Ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) ) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. Use according to claim 1, wherein the active ingredient is a compound of formula (III) or (IV). Use according to claim 6, wherein the active ingredient is 3- (3,4-difluorophenyl) -4- (4-methanesulfonyl-phenyl) -5H-furan-2-one or a pharmaceutically acceptable salt thereof. The use of claim 6, wherein the active ingredient is 4- (5-p-tolyl-3-trifluoromethyl-1H-pyrazol-1-yl) benzenesulfonamide or a pharmaceutically acceptable salt thereof. 9. Compounds of formula I or II in the formulas R ¹ is amino or -NHR ^a , where R ^a is an in vivo eliminable alkanoyl group; R ² is phenyl or phenyl substituted with at least one substituent selected from the group consisting of α-substituents and β-substituents as defined below; R ⁴ is C 1-6 alkyl; the α-substituents are C 1-6 alkoxy and C 1-6 alkylthio; and the β-substituents are selected from the group consisting of C 1-6 alkyl groups and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of tumor-related disorders in a mammal. HU 227 126 Β1 The use of claim 9, wherein R ¹ is amino or acetylamino. The use of claim 9, wherein the active ingredient is 4-methyl-2- (4-methylphenyl) -1- (4-sulphamoylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulphamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) - pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoyl) phenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (3,4-Dimethyl-phenyl) -4-methyl-1- (4-sulfamoyl-phenyl) -pyrrole, 4-methyl-1- (4-methyl-thiophenyl) -2- (4-Sun Ifamool l-phenyl I), 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3,5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (4-methoxy-phenyl) -pyrrole, and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. Use according to claim 9, wherein the active ingredient is 2- (4-Ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) ) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. 13. Compounds of formula I or II in the formulas R-ι is an amino group or -NHR is a group of ^the formula wherein R ^a is an in vivo eliminable alkanoyl group; R ² is phenyl or phenyl substituted with at least one substituent selected from the group consisting of α-substituents and β-substituents as defined below; R ⁴ is C 1-6 alkyl; the α-substituents are C 1-6 alkoxy and C 1-6 alkylthio; and the β-substituents include C 1-6 alkyl groups or pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for inhibiting tumor growth in a mammal. The use of claim 13, wherein R ¹ is amino or acetylamino. The use of claim 13, wherein the active ingredient is 4-methyl-2- (4-methylphenyl) -1- (4-sulphamoylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) - pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methyl-phenyl) -4-methyl-1- (4-sulfamoyl-phenyl) -pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulphamoylphenyl) pyrrole, pyrrole 4-methyl-1- (4-methylthio-phenyl) -2- (4-sulfamoyl-phenyl), 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulphamoylphenyl) pyrrole, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3,5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-Acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. The use of claim 13, wherein the active ingredient is 2- (4-Ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) ) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, or 1- (4-Acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole or a pharmaceutically acceptable salt thereof. 17. Compounds of formula I or II in the formulas R ¹ is amino or -NHR ^a , where R ^a is an in vivo eliminable alkanoyl group; R ² is phenyl or phenyl substituted with at least one substituent selected from the group consisting of α-substituents and β-substituents as defined below; R ⁴ is C 1-6 alkyl; the α-substituents are C 1-6 alkoxy and C 1-6 alkylthio; and the use of β-substituents containing from 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the inhibition of tumor metastasis in a mammal. The use of claim 17, wherein R ¹ is amino or acetylamino. The use of claim 17, wherein the active ingredient is 4-methyl-2- (4-methylphenyl) -1- (4-sulphamoylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) - pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-Ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoyl) phenyl) pyrrole, 2- (3,4-dimethyl-1-phenyl) -4-methyl-1- (4-sulfamoyl-phenyl) pyridine, pyrrole 4-methyl-1- (4-methylthio-phenyl) -2- (4-sulfamoyl-phenyl), 1- (3,4-dimethyl-1-phenyl) -4-methyl-2- (4-sulfamoyl-phenyl) pyridine, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3,5-Dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4 -methoxyphenyl) -pyrrole, and HU 227 126 Β1 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-phenyl) -pyrrole or a pharmaceutically acceptable salt thereof. The use of claim 17, wherein the active ingredient is 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulphamoylphenyl) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole and 1- (4-Acetylamino-sulfonyl-phenyl) -4-methyl-2- (3,4-dimethyl-5-phenyl) -pyrrole, or a pharmaceutically acceptable salt thereof.